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Published on: August 4, 2019
Arsenite inhibits p53 phosphorylation, DNA binding activity, and p53 target gene p21 expression in mouse epidermal
Faqing Tang1, Guangming Liu, Zhiwei He
1Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Abstract:
Epidemiologic investigations demonstrated that arsenite exposure increases the risk of various human cancers, including skin, lung, bladder, and kidney cancers. However, oral administration of arsenite alone has failed to induce tumors in animal models, suggesting that arsenic may act to enhance mutagenicity induced by other carcinogens. Arsenite may function as a co-carcinogen, acting by inhibiting repair of carcinogen-induced DNA damage mediated by p53 and p21, a p53 target gene. To elucidate the interaction between arsenite and p53 tumor suppressor protein, we studied the effect of arsenite on ultraviolet B (UVB)-induced p53 phosphorylation, p53 DNA binding activity, and p53-induced target gene transactivation in the JB6 Cl41 mouse epidermal skin cell model. Our results indicated that arsenite suppressed UVB-induced p53 phosphorylation and p53 DNA binding activity. Arsenite also inhibited casein kinase 2 (CK2) activity and decreased p53-regulated p21 protein expression. These data suggest that the direct inhibition of p53 functional activation is one of the mechanisms through which arsenite interferes with p53 function, and thus may be a significant mechanism for the co-carcinogenic effects of arsenite.
Insights
Arsenite exposure increases cancer risk by hindering DNA repair. This study shows arsenite inhibits p53 protein activation, a key tumor suppressor, potentially explaining its co-carcinogenic effects.
Area of Science:
- Environmental Health
- Molecular Biology
- Cancer Research
Background:
- Epidemiologic studies link arsenite exposure to increased human cancer risk.
- Arsenite alone does not induce tumors in animal models, suggesting a co-carcinogenic role.
- Arsenite may impair DNA damage repair pathways involving p53 and its target gene, p21.
Purpose of the Study:
- To investigate the interaction between arsenite and the p53 tumor suppressor protein.
- To determine arsenite's effect on ultraviolet B (UVB)-induced p53 activation in mouse epidermal cells.
Main Methods:
- Utilized the JB6 Cl41 mouse epidermal skin cell model.
- Assessed UVB-induced p53 phosphorylation and DNA binding activity.
- Measured casein kinase 2 (CK2) activity and p21 protein expression.
Main Results:
- Arsenite suppressed UVB-induced p53 phosphorylation and DNA binding.
- Arsenite inhibited CK2 activity.
- Arsenite decreased p53-regulated p21 protein expression.
Conclusions:
- Arsenite directly inhibits p53 functional activation.
- This inhibition of p53 is a potential mechanism for arsenite's co-carcinogenic effects.
- Arsenite interferes with crucial cellular pathways involved in tumor suppression.
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